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【结 构 式】 
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【分子编号】52384 【品名】{5-(2,3-bis{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}propyl)-4-(methyloxy)-3-[({[4-(methyloxy)phenyl]methyl}oxy)methyl]tetrahydro-2-furanyl}methanol 【CA登记号】 |
【 分 子 式 】C30H56O7Si2 【 分 子 量 】584.94144 【元素组成】C 61.6% H 9.65% O 19.15% Si 9.6% |
合成路线1
该中间体在本合成路线中的序号：(XXII)After silylation of diol (XII) to give (XIII), the O-benzyl group of (XIII) was removed by hydrogenolysis in the presence of Pearlman’s catalyst, yielding alcohol (XIV). Oxidation of alcohol (XIV) to the corresponding ketone (XV) was carried out by means of N-methylmorpholine-N-oxide in the presence of a catalytic amount of tetrapropylammonium perruthenate (TPAP). Ketone (XV) was then converted to the methylene derivative (XVI) by treatment with Tebbe's reagent, generated from bis(cyclopentadienyl)titanium and trimethylaluminum. Olefin (XVI) hydroboration by means of 9-borabicyclononane, followed by oxidative work-up with sodium perborate, provided the primary alcohol (XVII) as the undesired diastereoisomer. Configuration of alcohol (XVII) was inverted via Swern oxidation to the corresponding aldehyde, which was epimerized to (XVIII) under basic conditions. Further, aldehyde (XVIII) reduction with NaBH4 at 0 C generated alcohol (XIX). This was protected as the methoxybenzyl ether (XXI) by condensation with p-methoxybenzyl trichloroacetimidate (XX). The pivaloyl ester of (XXI) was then removed by reductive cleavage with LiAlH4, affording alcohol (XXII).
| 【1】 Littlefield, B.A.; Zheng, W.; Seletsky, B.M.; Yu, M.J.; Palme, M.H.; Towle, M.J. (Eisai Co., Ltd.); Macrocyclic analogs and methods of their use and preparation. US 6214865; WO 9965894 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XII) | 52375 | {5-(2,3-dihydroxypropyl)-4-(methyloxy)-3-[(phenylmethyl)oxy]tetrahydro-2-furanyl}methyl 2,2-dimethylpropanoate | C21H32O7 | 详情 | 详情 | |
| (XIII) | 52376 | {5-(2,3-bis{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}propyl)-4-(methyloxy)-3-[(phenylmethyl)oxy]tetrahydro-2-furanyl}methyl 2,2-dimethylpropanoate | C33H60O7Si2 | 详情 | 详情 | |
| (XIV) | 52377 | [5-(2,3-bis{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}propyl)-3-hydroxy-4-(methyloxy)tetrahydro-2-furanyl]methyl 2,2-dimethylpropanoate | C26H54O7Si2 | 详情 | 详情 | |
| (XV) | 52378 | [5-(2,3-bis{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}propyl)-4-(methyloxy)-3-oxotetrahydro-2-furanyl]methyl 2,2-dimethylpropanoate | C26H52O7Si2 | 详情 | 详情 | |
| (XVI) | 52379 | [(2R,4R,5R)-5-((2S)-2,3-bis{[tert-butyl(dimethyl)silyl]oxy}propyl)-4-methoxy-3-methylenetetrahydro-2-furanyl]methyl pivalate | C27H54O6Si2 | 详情 | 详情 | |
| (XVII) | 52380 | [(2R,3S,4R,5R)-5-((2S)-2,3-bis{[tert-butyl(dimethyl)silyl]oxy}propyl)-3-(hydroxymethyl)-4-methoxytetrahydro-2-furanyl]methyl pivalate | C27H56O7Si2 | 详情 | 详情 | |
| (XVIII) | 52381 | [(2R,3R,4R,5R)-5-((2S)-2,3-bis{[tert-butyl(dimethyl)silyl]oxy}propyl)-3-formyl-4-methoxytetrahydro-2-furanyl]methyl pivalate | C27H54O7Si2 | 详情 | 详情 | |
| (XIX) | 52382 | [5-(2,3-bis{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}propyl)-3-(hydroxymethyl)-4-(methyloxy)tetrahydro-2-furanyl]methyl 2,2-dimethylpropanoate | C27H56O7Si2 | 详情 | 详情 | |
| (XX) | 52385 | [4-(methyloxy)phenyl]methyl 2,2,2-trichloroethanimidoate | C10H10Cl3NO2 | 详情 | 详情 | |
| (XXI) | 52383 | {5-(2,3-bis{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}propyl)-4-(methyloxy)-3-[({[4-(methyloxy)phenyl]methyl}oxy)methyl]tetrahydro-2-furanyl}methyl 2,2-dimethylpropanoate | C35H64O8Si2 | 详情 | 详情 | |
| (XXII) | 52384 | {5-(2,3-bis{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}propyl)-4-(methyloxy)-3-[({[4-(methyloxy)phenyl]methyl}oxy)methyl]tetrahydro-2-furanyl}methanol | C30H56O7Si2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XXII)Homologation of alcohol (XXII) was effected by Swern oxidation to aldehyde (XXIII), which was then converted to the vinyl derivative (XXIV) by Wittig reaction with methylene triphenylphosphorane. Hydroboration of olefin (XXIV), followed by oxidative work-up, furnished alcohol (XXV). This was subjected to a further Swern oxidation to aldehyde (XXVI). Coupling of aldehyde (XXVI) with the known vinyl iodide (XXVII) produced a mixture of pyran derivative (XXVIII) and some uncyclized intermediate. Cyclization to (XXVIII) was completed by subsequent treatment of the reaction mixture with potassium hexamethyldisilazide. The p-methoxybenzyl protecting group of (XXVIII) was removed by oxidative treatment with DDQ. The desired diastereomer (XXIX) was then isolated by column chromatography.
| 【1】 Littlefield, B.A.; Zheng, W.; Seletsky, B.M.; Yu, M.J.; Palme, M.H.; Towle, M.J. (Eisai Co., Ltd.); Macrocyclic analogs and methods of their use and preparation. US 6214865; WO 9965894 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XXII) | 52384 | {5-(2,3-bis{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}propyl)-4-(methyloxy)-3-[({[4-(methyloxy)phenyl]methyl}oxy)methyl]tetrahydro-2-furanyl}methanol | C30H56O7Si2 | 详情 | 详情 | |
| (XXIII) | 52386 | 5-(2,3-bis{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}propyl)-4-(methyloxy)-3-[({[4-(methyloxy)phenyl]methyl}oxy)methyl]tetrahydro-2-furancarbaldehyde | C30H54O7Si2 | 详情 | 详情 | |
| (XXIV) | 52387 | 5-({5-ethenyl-3-(methyloxy)-4-[({[4-(methyloxy)phenyl]methyl}oxy)methyl]tetrahydro-2-furanyl}methyl)-2,2,3,3,8,8,9,9-octamethyl-4,7-dioxa-3,8-disiladecane; 2-(2,3-bis{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}propyl)-5-ethenyl-4-[({[4-(methyloxy)phenyl]methyl}oxy)methyl]tetrahydro-3-furanyl methyl ether | C31H56O6Si2 | 详情 | 详情 | |
| (XXV) | 52388 | 2-{5-(2,3-bis{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}propyl)-4-(methyloxy)-3-[({[4-(methyloxy)phenyl]methyl}oxy)methyl]tetrahydro-2-furanyl}-1-ethanol | C31H58O7Si2 | 详情 | 详情 | |
| (XXVI) | 52389 | 2-{5-(2,3-bis{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}propyl)-4-(methyloxy)-3-[({[4-(methyloxy)phenyl]methyl}oxy)methyl]tetrahydro-2-furanyl}acetaldehyde | C31H56O7Si2 | 详情 | 详情 | |
| (XXVII) | 52390 | 3-(5-{6-iodo-5-methyl-3-[(methylsulfonyl)oxy]-6-heptenyl}-4-methylidenetetrahydro-2-furanyl)propyl 2,2-dimethylpropanoate | C22H37IO6S | 详情 | 详情 | |
| (XXVIII) | 52391 | 3-[(2S,5S)-5-(2-{(2S,4R)-6-[((2S,3R,4R,5R)-5-((2S)-2,3-bis{[tert-butyl(dimethyl)silyl]oxy}propyl)-4-methoxy-3-{[(4-methoxybenzyl)oxy]methyl}tetrahydro-2-furanyl)methyl]-4-methyl-5-methylenetetrahydro-2H-pyran-2-yl}ethyl)-4-methylenetetrahydro-2-furanyl]propyl 2,2-dimethylpropanoate | C52H90O10Si2 | 详情 | 详情 | |
| (XXIX) | 52392 | 3-{5-[2-(6-{[5-(2,3-bis{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}propyl)-3-(hydroxymethyl)-4-(methyloxy)tetrahydro-2-furanyl]methyl}-4-methyl-5-methylidenetetrahydro-2H-pyran-2-yl)ethyl]-4-methylidenetetrahydro-2-furanyl}propyl 2,2-dimethylpropanoate | C44H82O9Si2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XXII)After silylation of diol (XII) to yield (XIII), the O-benzyl group of (XIII) was removed by hydrogenolysis in the presence of Pearlman’s catalyst, yielding alcohol (XIV). Oxidation of alcohol (XIV) to the corresponding ketone (XV) was carried out by means of N-methylmorpholine-N-oxide in the presence of a catalytic amount of tetrapropylammonium perruthenate (TPAP). Ketone (XV) was then converted to the methylene derivative (XVI) by treatment with Tebbe’s reagent, generated from bis(cyclopentadienyl)titanium and trimethylaluminum. Olefin (XVI) hydroboration by means of 9-borabicyclononane, followed by oxidative work-up with sodium perborate, provided the primary alcohol (XVII) as the undesired diastereoisomer. Configuration of alcohol (XVII) was inverted via Swern oxidation to the corresponding aldehyde, which was epimerized to (XVIII) under basic conditions. Further, aldehyde (XVIII) reduction with NaBH4 at 0 C generated alcohol (XIX). This was protected as the methoxybenzyl ether (XXI) by condensation with p-methoxybenzyl trichloroacetimidate (XX). The pivaloyl ester (XXI) was then removed by reductive cleavage with LiAlH4, affording alcohol (XXII).
| 【1】 Littlefield, B.A.; Zheng, W.; Seletsky, B.M.; Yu, M.J.; Palme, M.H.; Towle, M.J. (Eisai Co., Ltd.); Macrocyclic analogs and methods of their use and preparation. US 6214865; WO 9965894 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XII) | 52375 | {5-(2,3-dihydroxypropyl)-4-(methyloxy)-3-[(phenylmethyl)oxy]tetrahydro-2-furanyl}methyl 2,2-dimethylpropanoate | C21H32O7 | 详情 | 详情 | |
| (XIII) | 52376 | {5-(2,3-bis{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}propyl)-4-(methyloxy)-3-[(phenylmethyl)oxy]tetrahydro-2-furanyl}methyl 2,2-dimethylpropanoate | C33H60O7Si2 | 详情 | 详情 | |
| (XIV) | 52377 | [5-(2,3-bis{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}propyl)-3-hydroxy-4-(methyloxy)tetrahydro-2-furanyl]methyl 2,2-dimethylpropanoate | C26H54O7Si2 | 详情 | 详情 | |
| (XV) | 52378 | [5-(2,3-bis{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}propyl)-4-(methyloxy)-3-oxotetrahydro-2-furanyl]methyl 2,2-dimethylpropanoate | C26H52O7Si2 | 详情 | 详情 | |
| (XVI) | 52379 | [(2R,4R,5R)-5-((2S)-2,3-bis{[tert-butyl(dimethyl)silyl]oxy}propyl)-4-methoxy-3-methylenetetrahydro-2-furanyl]methyl pivalate | C27H54O6Si2 | 详情 | 详情 | |
| (XVII) | 52380 | [(2R,3S,4R,5R)-5-((2S)-2,3-bis{[tert-butyl(dimethyl)silyl]oxy}propyl)-3-(hydroxymethyl)-4-methoxytetrahydro-2-furanyl]methyl pivalate | C27H56O7Si2 | 详情 | 详情 | |
| (XVIII) | 52381 | [(2R,3R,4R,5R)-5-((2S)-2,3-bis{[tert-butyl(dimethyl)silyl]oxy}propyl)-3-formyl-4-methoxytetrahydro-2-furanyl]methyl pivalate | C27H54O7Si2 | 详情 | 详情 | |
| (XIX) | 52382 | [5-(2,3-bis{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}propyl)-3-(hydroxymethyl)-4-(methyloxy)tetrahydro-2-furanyl]methyl 2,2-dimethylpropanoate | C27H56O7Si2 | 详情 | 详情 | |
| (XX) | 52385 | [4-(methyloxy)phenyl]methyl 2,2,2-trichloroethanimidoate | C10H10Cl3NO2 | 详情 | 详情 | |
| (XXI) | 52383 | {5-(2,3-bis{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}propyl)-4-(methyloxy)-3-[({[4-(methyloxy)phenyl]methyl}oxy)methyl]tetrahydro-2-furanyl}methyl 2,2-dimethylpropanoate | C35H64O8Si2 | 详情 | 详情 | |
| (XXII) | 52384 | {5-(2,3-bis{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}propyl)-4-(methyloxy)-3-[({[4-(methyloxy)phenyl]methyl}oxy)methyl]tetrahydro-2-furanyl}methanol | C30H56O7Si2 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(XXII)Homologation of alcohol (XXII) was effected by Swern oxidation to aldehyde (XXIII), which was then converted to the vinyl derivative (XXIV) by Wittig reaction with methylene triphenylphosphorane. Hydroboration of olefin (XXIV), followed by oxidative work-up, furnished alcohol (XXV). This was subjected to a further Swern oxidation to aldehyde (XXVI). Coupling of aldehyde (XXVI) with the known vinyl iodide (XXVII) produced a mixture of pyran derivative (XXVIII) and some uncyclized intermediate. Cyclization to (XXVIII) was completed by subsequent treatment of the reaction mixture with potassium hexamethyldisilazide. The p-methoxybenzyl protecting group of (XXVIII) was removed by oxidative treatment with DDQ. The desired diastereomer (XXIX) was then isolated by column chromatography.
| 【1】 Littlefield, B.A.; Zheng, W.; Seletsky, B.M.; Yu, M.J.; Palme, M.H.; Towle, M.J. (Eisai Co., Ltd.); Macrocyclic analogs and methods of their use and preparation. US 6214865; WO 9965894 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XXII) | 52384 | {5-(2,3-bis{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}propyl)-4-(methyloxy)-3-[({[4-(methyloxy)phenyl]methyl}oxy)methyl]tetrahydro-2-furanyl}methanol | C30H56O7Si2 | 详情 | 详情 | |
| (XXIII) | 52386 | 5-(2,3-bis{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}propyl)-4-(methyloxy)-3-[({[4-(methyloxy)phenyl]methyl}oxy)methyl]tetrahydro-2-furancarbaldehyde | C30H54O7Si2 | 详情 | 详情 | |
| (XXIV) | 52387 | 5-({5-ethenyl-3-(methyloxy)-4-[({[4-(methyloxy)phenyl]methyl}oxy)methyl]tetrahydro-2-furanyl}methyl)-2,2,3,3,8,8,9,9-octamethyl-4,7-dioxa-3,8-disiladecane; 2-(2,3-bis{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}propyl)-5-ethenyl-4-[({[4-(methyloxy)phenyl]methyl}oxy)methyl]tetrahydro-3-furanyl methyl ether | C31H56O6Si2 | 详情 | 详情 | |
| (XXV) | 52388 | 2-{5-(2,3-bis{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}propyl)-4-(methyloxy)-3-[({[4-(methyloxy)phenyl]methyl}oxy)methyl]tetrahydro-2-furanyl}-1-ethanol | C31H58O7Si2 | 详情 | 详情 | |
| (XXVI) | 52389 | 2-{5-(2,3-bis{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}propyl)-4-(methyloxy)-3-[({[4-(methyloxy)phenyl]methyl}oxy)methyl]tetrahydro-2-furanyl}acetaldehyde | C31H56O7Si2 | 详情 | 详情 | |
| (XXVII) | 52390 | 3-(5-{6-iodo-5-methyl-3-[(methylsulfonyl)oxy]-6-heptenyl}-4-methylidenetetrahydro-2-furanyl)propyl 2,2-dimethylpropanoate | C22H37IO6S | 详情 | 详情 | |
| (XXVIII) | 52391 | 3-[(2S,5S)-5-(2-{(2S,4R)-6-[((2S,3R,4R,5R)-5-((2S)-2,3-bis{[tert-butyl(dimethyl)silyl]oxy}propyl)-4-methoxy-3-{[(4-methoxybenzyl)oxy]methyl}tetrahydro-2-furanyl)methyl]-4-methyl-5-methylenetetrahydro-2H-pyran-2-yl}ethyl)-4-methylenetetrahydro-2-furanyl]propyl 2,2-dimethylpropanoate | C52H90O10Si2 | 详情 | 详情 | |
| (XXIX) | 52392 | 3-{5-[2-(6-{[5-(2,3-bis{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}propyl)-3-(hydroxymethyl)-4-(methyloxy)tetrahydro-2-furanyl]methyl}-4-methyl-5-methylidenetetrahydro-2H-pyran-2-yl)ethyl]-4-methylidenetetrahydro-2-furanyl}propyl 2,2-dimethylpropanoate | C44H82O9Si2 | 详情 | 详情 |